ABSTRACT

BackgroundDiastolic dysfunction (DD) is known to be associated with increased mortality rate in the presence of impaired systolic function. However, few prognostic data exist regarding the effect of DD in patients with normal systolic function.

ResultsA total of 36 261 patients were identified (mean [SD] age, 58.3 [15.4] years; 54.4% female) with a mean (SD) follow-up time of 6.2 (2.3) years. In 65.2% of the cohort, DD was present, with mild DD being the most prevalent type of dysfunction. A total of 5789 deaths occurred during the follow-up period. The unadjusted survival rate was worse according to the presence and degree of DD (P <.001). However, after propensity matching, only moderate and severe DD were associated with an increased mortality risk (hazard ratio, 1.58; 95% confidence interval, 1.20-2.08; and hazard ratio, 1.84; 1.29-2.62, respectively; P <.001 for each).

ConclusionsIn this single-center study of patients with normal ejection fraction who presented for outpatient echocardiography, the presence of moderate or severe DD was an independent predictor of mortality. Mild DD, although prevalent, did not affect survival rate.

Figures in this Article

The noninvasive assessment of diastolic function is an integral component of any examination of the heart via echocardiography.1,2 When diastolic dysfunction (DD) is present, it is typically graded as mild, moderate, or severe; this grading system has been used to assess the prognostic relevance of its presence.1 Severe DD has been associated with an increased risk of mortality in many conditions, including post–acute myocardial infarction,3,4 amyloidosis,5 hypertension,6 chronic renal failure,7 and systolic impairment,8- 11 and even in the presence of normal systolic function in some populations.12- 14 However, because many of the medical conditions associated with DD, such as hypertension, coronary artery disease, increasing age, obesity, and diabetes mellitus,14- 16 are predictors of mortality, the question arises as to whether DD is truly an independent prognostic indicator of outcome in the setting of preserved systolic function. Furthermore, although mild DD is more prevalent clinically, fewer data are available regarding its prognostic significance.12,14,17 We therefore sought to address the clinical relevance of the presence of DD and the degree of DD in patients with normal ejection fraction undergoing outpatient echocardiography, one of the most commonly used cardiac noninvasive imaging tests in the United States.18

METHODS

STUDY DESIGN

The study cohort consisted of consecutive patients who underwent an outpatient echocardiographic test with normal systolic function results, as defined by an ejection fraction of 55% or greater, at the Cleveland Clinic or its satellite outpatient facilities from January 1, 1996, through December 31, 2005. Patients were excluded if a valid US Social Security Number was not available, if diastolic function could not be assessed, or if severe mitral valve disease was present or prior mitral valve surgery had occurred. Inability to assess diastolic function was common in certain clinical scenarios such as in patients with tachycardia, patients with severe lung disease with limited acoustic windows for echocardiographic testing, and patients in whom echocardiographic testing was performed on an urgent basis. If a patient had undergone more than 1 study, only results from the first was included in the analysis.

During the study period, 36 261 patients were included from a total of 65 696 echocardiographic tests performed (Figure 1). The survival rate of patients who were excluded for reasons other than an unavailable US Social Security Number was not different from that of patients who were included (log-rank P = .20).

ECHOCARDIOGRAPHIC METHODS

Diastolic function was assessed in a standard manner at our institution in accordance with relevant guidelines by using a combination of echocardiographic variables, including transmitral inflow pattern, pulmonary venous flow pattern, and, beginning in the late 1990s and almost uniformly after 2001, mitral annular velocities as assessed by tissue Doppler imaging.19 In patients with atrial fibrillation, diastolic stage was assessed when possible using a combination of variables, including transmitral inflow pattern (ie, deceleration time of mitral E wave velocity)20 and tissue Doppler imaging (ie, peak early mitral inflow velocity/diastolic early tissue velocity [E/e′]).21

With the use of these variables, function was deemed normal or abnormal in the study population. Then DD was graded in a standard manner as being mild (grade I, ie, impaired relaxation pattern), moderate (grade II, ie, pseudonormal pattern), or severe (grade III, ie, restrictive filling pattern) dysfunction, as previously described.2 Mild DD is typified by abnormal myocardial relaxation with normal left atrial pressures. In moderate and severe DD, increases in mean left atrial pressures occur in addition to impairment of left ventricular relaxation and compliance. Systolic function was assessed by a semiquantitative evaluation of ejection fraction by an experienced reader (among them, W.A.J. and J.D.T.), in accordance with published guidelines.22 The interobserver agreement for reproducibility of DD classification extrapolated from our ongoing quality assurance effort was, on average, 83.0% and intraobserver agreement was 94.0%.

CLINICAL DATA

Clinical data were obtained from review of electronic medical records recorded from a period starting 6 months before the echocardiographic testing date and ending 6 months afterward. The clinical diagnosis of conditions, including coronary artery disease, peripheral vascular disease, atrial fibrillation, diabetes mellitus, hypertension, congestive heart failure (CHF), dyslipidemia, chronic obstructive pulmonary disease, and chronic renal failure, was established by reviewing records documented by a providing physician in an electronic medical record system (EpicCare; Epic Systems Corporation, Madison, Wisconsin) that was then linked to relevant International Classification of Diseases, Ninth Revision (ICD-9) codes (eTable). All diagnoses (primary and nonprimary) and encounters (inpatient and outpatient) were considered, and only 1 code was required to fulfill the criteria for a given diagnosis. Individual all-cause mortality was obtained using the Social Security Death Index with a previously reported high degree of specificity.23 The censoring date was December 14, 2009. The study was conducted with the approval of the Cleveland Clinic institutional board review with waiver of consent.

STATISTICAL ANALYSES

Continuous data are expressed as mean (SD), with median and 15th and 85th percentile values (comparable to 1 SD). Kruskal-Wallis tests were used to analyze group differences for the continuous data. Categorical data are displayed as frequencies and percentages, and comparisons are made using χ2 tests (and Fisher exact tests if appropriate).

Several factors differentiated the patients in the 4 groups. To evaluate survival with more comparable patients among the diastolic stages, we used propensity matching.24- 26 Multivariable logistic regression analyses were used to determine factors related to severe DD compared with each of the other groups. For continuous variables, investigations of transformations of scale were used (log, inverse, and exponential) to properly calibrate the effects with outcome. Because of imbalance in group sizes, a model was developed for each stage vs the 127 patients with severe DD. The logistic models yielded a propensity score for inclusion in the severe DD group. Using the propensity scores, many-to-1 matching was used to find the maximum number of matches of the 127 severe DD cases for each comparison group using greedy matching of closest matches within a maximum distance of 0.1.

After matching, data from patients were sorted based on propensity scores and divided into quintiles. Characteristics were evaluated to ensure balanced factors in the groups within similar propensity score ranges. Propensity matching was performed using the variables listed in Table 1. The propensity models incorporated each of the variables regardless of their significance.

Overall and stratified nonparametric survival estimates were obtained via the method created by Kaplan and Meier.27 A parametric method was used to resolve the number of phases of instantaneous risk for death (ie, hazard function) and to estimate the shaping variables.25

The degree of DD as a single covariate was forced into the final parametric model for all patients and for the matched cohort of patients. Statistical analyses were performed using SAS statistical software, version 9 (SAS Institute Inc, Cary, North Carolina).

RESULTS

PATIENT CHARACTERISTICS

A total of 36 261 patients were identified (mean [SD] age, 58.3 [15.4] years; 54.4% female), with a mean (SD) follow-up time of 6.2 (2.3) years. Clinical characteristics, including indication for performing echocardiographic testing, are presented in Table 1 and reflect typical characteristics of patients referred for outpatient echocardiographic testing at our institution. Cardiovascular risk factors, such as dyslipidemia, hypertension, and diabetes mellitus, were seen in 35.3%, 14.9%, and 11.6% of patients, respectively. However, established cardiovascular disease, such as CHF, coronary artery disease, and peripheral vascular disease, was uncommon, affecting 3.5%, 0.6%, and 1.1%, respectively. The 5 most common indications included evaluation of symptoms (21.3%), assessment of ventricular function (19.7%), assessment of valvular function (11.6%), suspected or known coronary artery disease (9.8%), and arrhythmia or electrocardiographic abnormalities (17.9%) (Table 1).

DIASTOLIC FUNCTION

In 65.2% of the cohort, DD was present, with mild DD being the most prevalent type of dysfunction (60.0% mild DD, 4.8% moderate DD, and 0.4% severe DD). Patients with DD were more likely to be male, older than 65 years, and obese (body mass index [calculated as weight in kilograms divided by height in meters squared] > 30). They also were more likely to have cardiovascular risk factors and established cardiovascular disease (all P <.001) (Table 1). Although noncardiac chronic medical conditions such as chronic obstructive pulmonary disease and chronic renal failure were uncommon (3.1% and 1.5%, respectively), patients with these conditions also were more likely to have DD (P <.001 for each).

MORTALITY AND DIASTOLIC FUNCTION

During the follow-up period, 5789 deaths occurred: 842 in the normal diastolic function group (representing 7.0% of the patients with normal diastolic function), 4469 (21.0%) in the mild DD group, 429 (24.0%) in the moderate DD group, and 49 (39.0%) in the severe DD group. The unadjusted survival rate was worse in patients with DD, and this risk was greater with worsening degrees of DD (P <.001).

After propensity matching was performed, data from a resulting group of 1249 patients were used in subsequent analysis. Clinical characteristics of the matched patient population according to diastolic function stage are listed in Table 2.

Kaplan-Meier analysis of survival in 1249 propensity-matched patients who had an outpatient echocardiographic result with normal systolic function (ejection fraction ≥ 55%) from January 1, 1996, to December 31, 2005, stratified according to diastolic function stage. DD indicates diastolic dysfunction.

COMMENT

A high prevalence (65.0%) of DD was observed in our cohort with normal ejection fraction who presented for outpatient echocardiographic testing. Although DD was associated with the presence of cardiovascular risk factors and cardiovascular disease, the overall prevalence of established disease and particularly CHF was low. Unadjusted survival was worse according to the presence and degree of DD, but after propensity matching, only moderate and severe DD were independent predictors of mortality. For the first time, to our knowledge, moderate and severe DD have been shown to be independent predictors of mortality rate, although mild DD has not shown this characteristic after adjusting for common cardiovascular risk factors and existing comorbidities in a large cohort of outpatients with normal ejection fraction. This finding has important clinical implications, especially given the high prevalence of mild DD in the population studied.

Because the link between DD and mortality rate in impaired systolic function is well established,8- 11 we sought to study the prevalence and outcome of DD specifically in a cohort with a normal ejection fraction. We chose to include patients with CHF because the precise underlying pathophysiologic cause of heart failure with preserved ejection fraction is still debated, and abnormalities in these patients include abnormal left ventricular systolic properties; ventricular-arterial coupling; left ventricular diastolic function, torsion, or twist; ventricular-ventricular interaction; pericardial constraint with impaired chronotropic vasodilator reserves; and pulmonary hypertension.28 Furthermore, in a recent study29 of patients with normal systolic function and moderate or severe DD, the rate of progression to clinical heart failure for 2 years was low, although a moderate rate of progression in the development of symptoms and cardiac hospitalizations occurred.

In fact, in our cohort, the prevalence of CHF and therefore of heart failure with preserved ejection fraction was low, as was the prevalence of other cardiac diseases. Therefore, because the overall prevalence of DD was high, most patients who presented for outpatient echocardiographic testing in our institution had, by definition,14,17,29,30 preclinical DD. Because the use of echocardiography as a clinical tool in the outpatient setting continues to increase, with an estimated 9 million echocardiographic tests performed in 2004 in the US Medicare system,18 our study provides the physician with a prognostic context when DD is reported, especially because most procedures are requested by noncardiologists.18

Prior studies have demonstrated increased mortality from DD in patients with normal systolic function but have varied in characterizing the degree of risk according to the stage of DD. A large community cohort demonstrated increased mortality associated with mild or moderate and severe DD independent of age, ejection fraction, and sex but without adjustment for other comorbidities.14 However, in a cohort of 3008 middle-aged or elderly American Indian men (ie, the second Strong Heart Study), although mild DD was associated with an increase in all-cause and cardiac mortality, this increase was not independent of other comorbidities.13 A recent cohort study12 of 735 patients with an ejection fraction greater than 45% found that severe DD was an independent predictor of mortality in addition to age, hyperlipidemia, and the presence of a comorbid illness. All these studies had a DD prevalence of less than 30%, in contrast to the current study. In addition, women were underrepresented in some studies.12,13 Our study overcame some of the limitations of preceding studies by including a large sex-balanced population with representation and targeted analysis of all stages of DD and a true normal ejection fraction (≥55%). In this setting, we identified moderate and severe DD as independent predictors of worse survival rate. Contrary to the largest study to date,14 mild DD was not associated with increased mortality rate.

The potential mechanisms by which moderate and severe DD independently confer mortality risk require further study to identify whether a targeted therapeutic approach directed at DD can be found. However, our results suggest that an increased awareness of the clinical significance of advanced DD may lead to earlier identification of those patients who are at risk, especially at a preclinical stage.

Limited data exist regarding the natural history of DD and specifically regarding whether progression among stages exists over time. One study has demonstrated that in patients with DD and ejection fractions greater than 45%, the condition of approximately half of patients remained stable, 21% displayed improvement, and 27% deteriorated clinically during a follow-up of 3.6 years.12 A mortality benefit was observed in those whose DD improved compared with those whose DD remained the same or had deteriorated clinically. Further investigation is warranted to understand the natural history of DD and the factors that affect progression.

Our study had several limitations. It is a retrospective study from a single institution. Also, the assessment of diastolic function using Doppler echocardiographic testing is performed in a standard manner in our institution, but the use of tissue Doppler to assess mitral annular velocities only began in the late 1990s. Individual patient histories were unmasked to the reader when interpreting the echocardiographic results. Systolic function was assessed using the ejection fraction, which is an imperfect but universally understood variable used in a manner consistent with those of prior studies of diastolic dysfunction. The outcome studied was all-cause mortality, which is clinically relevant, objective, and nonbiased compared with cardiac-specific causes of death,23 but we do not report clinical events before death.

We recorded clinical data from a period starting 6 months before the echocardiographic testing date and ending 6 months afterward, thus representing only a brief period. Therefore, relevant clinical diagnoses before or after the interval and subsequent changes in medical regimen were not captured. Furthermore, clinical data were obtained by review of electronic medical records and linking to relevant ICD-9 codes, which can have limited sensitivity.31 The propensity matching did not include certain unmeasured variables or unobserved variables, such as history of cancer and severity of native valve disease; therefore, potential confounding by these variables cannot be excluded.

In a single-center cohort of patients with normal ejection fraction referred for outpatient echocardiographic testing for a variety of indications, DD, especially mild DD, was highly prevalent. After adjustment for a number of cardiac and noncardiac comorbidities, moderate and severe DD were independent predictors of mortality during follow-up but mild DD was not. Further studies are required to identify the precise mechanistic linkage between advanced DD and mortality rate.

Author Contributions: Drs Halley, Khalil, and Jaber had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Halley and Jaber. Acquisition of data: Halley, Khalil, and Jaber. Analysis and interpretation of data: Halley, Houghtaling, Thomas, and Jaber. Drafting of the manuscript: Halley and Jaber. Critical revision of the manuscript for important intellectual content: Halley, Houghtaling, Khalil, Thomas, and Jaber. Statistical analysis: Halley and Houghtaling. Administrative, technical, and material support: Khalil, Thomas, and Jaber. Study supervision: Thomas and Jaber.

Financial Disclosure: Dr Thomas has served as a consultant to and received honoraria from GE Healthcare, Philips Healthcare, and Siemens AG (none within the past year).

Quiñones
MAOtto
CMStoddard
MWaggoner
AZoghbi
WADoppler Quantification Task Force of the Nomenclature and Standards Committee of the American Society of Echocardiography, Recommendations for quantification of Doppler echocardiography: a report from the Doppler Quantification Task Force of the Nomenclature and Standards Committee of the American Society of Echocardiography. J Am Soc Echocardiogr 2002;15
(2)
167- 184PubMed

Lang
RMBierig
MDevereux
RB
et al. Chamber Quantification Writing Group; American Society of Echocardiography's Guidelines and Standards Committee; European Association of Echocardiography, Recommendations for chamber quantification: a report from the American Society of Echocardiography's Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005;18
(12)
1440- 1463PubMed

Hunt
SAAbraham
WTChin
MH
et al. 2009 focused update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation. Circulation 2009;119
(14)
e391- e479PubMed10.1161/CIRCULATIONAHA.109.192065

Kaplan-Meier analysis of survival in 1249 propensity-matched patients who had an outpatient echocardiographic result with normal systolic function (ejection fraction ≥ 55%) from January 1, 1996, to December 31, 2005, stratified according to diastolic function stage. DD indicates diastolic dysfunction.

Quiñones
MAOtto
CMStoddard
MWaggoner
AZoghbi
WADoppler Quantification Task Force of the Nomenclature and Standards Committee of the American Society of Echocardiography, Recommendations for quantification of Doppler echocardiography: a report from the Doppler Quantification Task Force of the Nomenclature and Standards Committee of the American Society of Echocardiography. J Am Soc Echocardiogr 2002;15
(2)
167- 184PubMed

Lang
RMBierig
MDevereux
RB
et al. Chamber Quantification Writing Group; American Society of Echocardiography's Guidelines and Standards Committee; European Association of Echocardiography, Recommendations for chamber quantification: a report from the American Society of Echocardiography's Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005;18
(12)
1440- 1463PubMed

Hunt
SAAbraham
WTChin
MH
et al. 2009 focused update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation. Circulation 2009;119
(14)
e391- e479PubMed10.1161/CIRCULATIONAHA.109.192065

Correspondence

The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.
The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with
the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.

Indicate what change(s) you will implement in your practice, if any, based on this CME course.

Your quiz results:

The filled radio buttons indicate your responses. The preferred responses are highlighted

For CME Course:
A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes

Indicate what changes(s) you will implement in your practice, if any, based on this
CME course.

Instructions

Thank you for submitting a comment on this article. It will be reviewed by JAMA Internal Medicine editors. You will be notified when your comment has been published. Comments should not exceed 500 words of text and 10 references.

Do not submit personal medical questions or information that could identify a specific patient, questions about a particular case, or general inquiries to an author. Only content that has not been published, posted, or submitted elsewhere should be submitted. By submitting this Comment, you and any coauthors transfer copyright to the journal if your Comment is posted.

* = Required Field

Comment Author(s)* (if multiple authors, separate
names by comma)

Example: John Doe

Affiliation & Institution*

Disclosure of Any Conflicts of Interest*
Indicate all relevant conflicts of interest of each author below, including all relevant financial interests, activities, and relationships within the past 3 years including, but not limited to, employment, affiliation, grants or funding, consultancies, honoraria or payment, speakers’ bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued. If all authors have none, check "No potential conflicts or relevant financial interests" in the box below. Please also indicate any funding received in support of this work. The information will be posted with your response.

This feature is provided as a courtesy. By using it you agree that that you are requesting the material solely for personal, non-commercial use, and that it is subject to the AMA's Terms of Use. The information provided in order to email this article will not be shared, sold, traded, exchanged, or rented. Please refer to The JAMA Network's Privacy Policy for additional information.

Athens and Shibboleth are access management services that provide single sign-on to protected resources. They replace the multiple user names and passwords necessary to access subscription-based content with a single user name and password that can be entered once per session. It operates independently of a user's location or IP address. If your institution uses Athens or Shibboleth authentication, please contact your site administrator to receive your user name and password.

What is this ?

Article rental gives users the ability to access the full text of an article and its supplementary content for 24 hours.
Access to the PDF is only available via article purchase.